Non-coding rna for subtyping of bladder cancer

Abstract

The present disclosure pertains to the field of personalized medicine and methods for treating bladder cancer. In some embodiments, the disclosure relates to the use of long non-coding RNA (lncRNA) and genomic signatures for the prognosis of individuals with bladder cancer. The present disclosure provides methods for subtyping bladder cancer. The present disclosure also provides methods and compositions for treating bladder cancer.

What is claimed is: 
     
         1 . A method comprising:
 a) providing a biological sample from a subject having bladder cancer;   b) measuring levels of expression in the biological sample of a plurality of genes selected from Table 2 and/or Table 5; and   c) subtyping the bladder cancer of the subject according to a genomic subtyping classifier based on the levels of expression of the plurality of genes, wherein said subtyping comprises assigning the bladder cancer to one of five subtypes selected from the group consisting of basal/squamous, luminal, luminal-infiltrated, luminal-papillary, and neuronal subtype.   
     
     
         2 . The method of  claim 1 , further comprising determining that the subject has a favorable prognosis if the subtyping indicates that the subject has the luminal-papillary subtype or determining that the subject has an unfavorable prognosis if the subtyping indicates that the subject has the basal/squamous, luminal, luminal-infiltrated, or neuronal subtype. 
     
     
         3 . The method of  claim 1  or  2 , further comprising determining that the subject has a less aggressive tumor if the subtyping indicates that the subject has the luminal-papillary subtype or determining that the subject has a more aggressive tumor if the subtyping indicates that the subject has the basal/squamous, luminal, luminal-infiltrated, or neuronal subtype. 
     
     
         4 . The method of any one of  claims 1 - 3 , further comprising administering an FGFR3 inhibitor to the subject if the subtyping indicates that the subject has the luminal-papillary subtype and administering neoadjuvant chemotherapy to the subject if the subtyping indicates that the subject has the basal/squamous, luminal, luminal-infiltrated, or neuronal subtype. 
     
     
         5 . A method for treating a subject with bladder cancer, the method comprising:
 determining the subtype of bladder cancer the subject has by:
 obtaining or having obtained a biological sample from the subject; 
 measuring or having measured the levels of expression in the biological sample of a plurality of genes selected from Table 2 and/or Table 5; and 
 assigning the bladder cancer to one of five subtypes selected from the group consisting of basal/squamous, luminal, luminal-infiltrated, luminal-papillary, and neuronal subtype based on the levels of expression of the plurality of genes; and 
   if the subject has luminal-papillary subtype, then administering an FGFR3 inhibitor, and   if the subject has basal/squamous, luminal, luminal-infiltrated, or neuronal subtype, then administering to the subject neoadjuvant chemotherapy.   
     
     
         6 . The method of  claim 4  or  5 , wherein the neoadjuvant chemotherapy comprises administering cisplatin. 
     
     
         7 . The method of any one of  claims 1 - 6 , wherein the method is performed prior to treatment of the patient with anti-cancer therapy. 
     
     
         8 . The method of any one of  claims 1 - 6 , wherein the subject is undergoing anti-cancer therapy. 
     
     
         9 . The method of any one of  claims 1 - 8 , wherein the subject has muscle-invasive bladder cancer. 
     
     
         10 . The method of any one of  claims 1 - 9 , wherein the biological sample is a biopsy. 
     
     
         11 . The method of any one of  claims 1 - 9 , wherein the biological sample is a urine sample, a blood sample, or a bladder tumor sample. 
     
     
         12 . The method of any one of  claims 1 - 9 , wherein the biological sample is a transurethral resection (TUR) specimen. 
     
     
         13 . The method of any one of  claims 1 - 12 , wherein the subject is a human being. 
     
     
         14 . The method of any one of  claims 1 - 13 , wherein the level of expression is increased or reduced compared to a control. 
     
     
         15 . The method of any one of  claims 1 - 14 , wherein said measuring levels of expression comprises performing in situ hybridization, a PCR-based method, a sequencing method, an array-based method, an immunohistochemical method, an RNA assay method, or an immunoassay method. 
     
     
         16 . The method of any one of  claims 1 - 15 , wherein said measuring levels of expression comprises using a reagent selected from the group consisting of a nucleic acid probe, one or more nucleic acid primers, and an antibody. 
     
     
         17 . The method of any one of  claims 1 - 16 , wherein said measuring levels of expression comprises measuring the level of an RNA transcript. 
     
     
         18 . The method of  claim 17 , wherein the RNA is long non-coding RNA. 
     
     
         19 . The method of any one of  claims 1 - 18 , wherein the bladder cancer is FGFR3 positive. 
     
     
         20 . The method of any one of  claims 1 - 19 , further comprising administering at least one anti-cancer therapy selected from the group consisting of an FGFR3 inhibitor, surgery, radiation therapy, immunotherapy, biological therapy, hormonal therapy, and photodynamic therapy. 
     
     
         21 . A method for determining a treatment for a subject who has bladder cancer, the method comprising:
 a) providing a biological sample from the subject;   b) detecting the presence or expression level in the biological sample for a plurality of targets selected from Table 2 and/or Table 5;   c) subtyping the bladder cancer of the subject according to a genomic subtyping classifier based on the levels of expression of the plurality of genes, wherein said subtyping comprises assigning the bladder cancer to one of five subtypes selected from the group consisting of basal/squamous, luminal, luminal-infiltrated, luminal-papillary, and neuronal subtype; and   d) determining whether or not the subject is likely to be responsive to anti-cancer therapy based on the subtype of the bladder cancer in the subject; and   e) prescribing anti-cancer therapy to the subject if the patient is identified as likely to be responsive to anti-cancer therapy.   
     
     
         22 . The method of  claim 21 , wherein the anti-cancer therapy is an FGFR3 inhibitor. 
     
     
         23 . A kit for prognosing bladder cancer in a subject, the kit comprising agents for detecting the presence or expression levels for a plurality of targets, wherein said plurality of genes comprises one or more genes selected from Table 2 and/or Table 5. 
     
     
         24 . The kit of  claim 23 , wherein said agents comprise reagents for performing in situ hybridization, a PCR-based method, an array-based method, a sequencing method, an immunohistochemical method, an RNA assay method, or an immunoassay method. 
     
     
         25 . The kit of  claim 23  or  24 , wherein said agents comprise one or more of a microarray, a nucleic acid probe, a nucleic acid primer, or an antibody. 
     
     
         26 . The kit of any one of  claims 23 - 25 , wherein the kit comprises at least one set of PCR primers capable of amplifying a nucleic acid comprising a sequence of a gene selected from Table 2 and/or Table 5 or its complement. 
     
     
         27 . The kit of any one of  claims 23 - 26 , wherein the kit comprises at least one probe capable of hybridizing to a nucleic acid comprising a sequence of a gene selected from Table 2 and/or Table 5 or its complement. 
     
     
         28 . The kit of any one of  claims 23 - 27 , further comprising information, in electronic or paper form, comprising instructions on how to determine if a subject is likely to be responsive to anti-cancer therapy. 
     
     
         29 . The kit of any one of  claims 23 - 28 , further comprising one or more control reference samples. 
     
     
         30 . A probe set for prognosing bladder cancer in a subject, the probe set comprising a plurality of probes for detecting a plurality of target nucleic acids, wherein the plurality of target nucleic acids comprises one or more gene sequences, or complements thereof, of genes selected from Table 2 and/or Table 5. 
     
     
         31 . The probe set of  claim 30 , wherein at least one probe is detectably labeled. 
     
     
         32 . A kit for prognosing prostate cancer comprising the probe set of  claim 30  or  31 . 
     
     
         33 . A system for analyzing a bladder cancer to provide a prognosis to a subject having bladder cancer, the system comprising:
 a) the probe set of  claim 30  or  31 ; and   b) a computer model or algorithm for analyzing an expression level or expression profile of the plurality of target nucleic acids hybridized to the plurality of probes in a biological sample from a subject who has bladder cancer and subtyping the bladder cancer of the subject according to a genomic subtyping classifier based on the expression level or expression profile, wherein said subtyping comprises assigning the bladder cancer to one of five subtypes selected from the group consisting of basal/squamous, luminal, luminal-infiltrated, luminal-papillary, and neuronal subtype.   
     
     
         34 . A kit for prognosing prostate cancer in a subject comprising the system of  claim 33 . 
     
     
         35 . The kit of  claim 34 , further comprising a computer model or algorithm for designating a treatment modality for the subject. 
     
     
         36 . The kit of  claim 34  or  35 , further comprising a computer model or algorithm for normalizing the expression level or expression profile of the plurality of target nucleic acids. 
     
     
         37 . A method for treating a subject with bladder cancer, the method comprising: a) providing a biological sample from a subject having bladder cancer; b) detecting the presence or expression level in the biological sample for a plurality of targets selected from Table 2 and/or Table 5; and c) administering a treatment to the subject, wherein the treatment is selected from the group consisting of neoadjuvant chemotherapy or an anti-cancer treatment. 
     
     
         38 . The method of  claim 37 , wherein the anti-cancer treatment is selected from the group consisting of surgery, chemotherapy, radiation therapy, immunotherapy, biological therapy, hormonal therapy, and photodynamic therapy. 
     
     
         39 . The method of  claim 37  or  38 , further comprising subtyping the bladder cancer in the subject according to a genomic subtyping classifier based on the presence or expression levels of the plurality of targets, wherein said subtyping comprises assigning the bladder cancer to one of five subtypes selected from the group consisting of basal/squamous, luminal, luminal-infiltrated, luminal-papillary, and neuronal subtype.